title: Novel CYP2D6 and CYP2C19 variants identified in a patient with adverse reactions towards venlafaxine monotherapy and dual therapy with nortriptyline and fluoxetine.
abstract: We present a case report of novel variants of CYP2D6 and CYP2C19 identified in a patient who experienced adverse effects during antidepressant therapy. CYP2D6 DNA sequencing revealed that the patient was most likely an intermediate metabolizer, owing to the presence of a novel variant (2579C>T), which gives rise to a premature stop codon in exon 5. Because defects in CYP2C19 may also be important, we sequenced the promoter region and all exons of CYP2C19 and identified a cluster of three novel variants (-13G>A, 7C>T and 10T>C) around exon 1, as well as the more common CYP2C19*2 allele. The presence of multiple genetic lesions in CYP2C19 implies that this patient is potentially a CYP2C19 poor metabolizer, and this was confirmed by haplotype analysis. Combined impairment of CYP2D6 and CYP2C19 activities, we believe, may have contributed to the development of the observed drug responses in the present report.
authors.affiliation: Department of Pathology and Carney Centre for Pharmacogenomics, University of Otago, Christchurch, New Zealand.
authors.forename: Eng Wee
authors.initials: EW
authors.lastname: Chua
authors.forename: James
authors.initials: J
authors.lastname: Foulds
authors.forename: Allison L
authors.initials: AL
authors.lastname: Miller
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kennedy
mesh_terms: D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000009:adverse effects*; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D003511:Cyclohexanols / Q000008:administration & dosage / Q000009:adverse effects*; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000009:adverse effects*; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D009661:Nortriptyline / Q000008:administration & dosage / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D000069470:Venlafaxine Hydrochloride; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D005473:Fluoxetine; D000069470:Venlafaxine Hydrochloride; D009661:Nortriptyline; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6